Serum hepatocyte growth factor and cancer mortality in an apparently healthy Japanese population.

BACKGROUND: In patients with cancer, hepatocyte growth factor (HGF) is elevated and is a predictor of prognosis. We investigated whether serum HGF was a predictive marker for cancer death in a population of community-dwelling Japanese. METHODS: We studied 1492 apparently healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of liver disease or malignancy on a baseline questionnaire were excluded, and plasma HGF was measured in the remaining 1470 participants, who were followed periodically for 10 years. Multivariate proportional hazards regression was used to estimate cancer mortality. RESULTS: A total of 169 participants died during follow-up (61 from cancer, 32 from cerebrocardiovascular disease, and 76 from other diseases). Mean HGF at baseline was significantly higher among decedents than among survivors (0.26 ± 0.11 vs 0.23 ± 0.09 ng/ml, respectively; P < 0.01). The Cox proportional hazards model showed that age, systolic blood pressure, HGF (hazard ratio, 1.27; 95% CI, 1.06-1.52; P = 0.009), albumin level, smoking status, and creatinine were independent predictors of all-cause death. Age, HGF (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = 0.02), and total cholesterol were independent predictive markers for cancer death. CONCLUSIONS: Serum HGF was a predictor of cancer death in an apparently healthy population of community-dwelling Japanese.

Factors associated with plasma ghrelin level in Japanese general population.

OBJECTIVE: Ghrelin is a novel gastric peptide identified in 1999 as a 'hunger hormone'. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. METHODS: Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005-2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. RESULTS: In our population, the mean BMI was 23·8 kg/m(2) , indicating a nonobese population. Results of univariate analysis showed that age (P<0·001), BMI (P<0·001), waist (P<0·001), triglycerides (P<0·01), FPG (P<0·01), insulin (P<0·001) and uric acid (P<0·05) were inversely associated with ghrelin. High-density lipoprotein (HDL) cholesterol (P<0·001) and eGFR (P<0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P<0·001). Results of the multiple stepwise regression analysis revealed that age (P<0·001; inversely), female gender (P<0·001), insulin (P<0·001; inversely), HDL cholesterol (P=0·005), BMI (P=0·01; inversely) and uric acid (P=0·045; inversely) were significantly and independently associated with ghrelin. CONCLUSIONS: The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.

Plasma level of asymmetric dimethylarginine (ADMA) as a predictor of carotid intima-media thickness progression: six-year prospective study using carotid ultrasonography.

This study was designed to determine the relationship between plasma asymmetric dimethylarginine (ADMA) and the development of carotid atherosclerosis. Cross-sectional studies have revealed that plasma ADMA concentration is correlated with the intima-media thickness (IMT) of the carotid artery, but no prospective studies have appeared. Therefore we prospectively investigated whether or not plasma ADMA level can predict IMT progression. In a community-based cohort, we enrolled 712 subjects who were over 40 years old and who had no apparent cardiovascular diseases according to high-resolution carotid ultrasonography. Blood chemistries including ADMA were measured at baseline. In 575 subjects, IMT was re-measured 6 years later. The value of baseline ADMA for predicting IMT changes was investigated by multivariable analysis. At baseline, there was a significant (beta=0.321; p<0.001) relationship between IMT and ADMA levels. Multiple linear regression analysis revealed that baseline ADMA (beta=0.241; p<0.01) was the only predictor of IMT progression after adjustments for age, sex, baseline IMT, and four major risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking) plus hyperuricacidemia. Plasma ADMA was a predictor of carotid IMT progression.

LDL-C/HDL-C Ratio Predicts Carotid Intima-Media Thickness Progression Better Than HDL-C or LDL-C Alone.

High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are strong predictors of atherosclerosis. Statin-induced changes in the ratio of LDL-C to HDL-C (LDL-C/HDL-C) predicted atherosclerosis progression better than LDL-C or HDL-C alone. However, the best predictor of subclinical atherosclerosis remains unknown. Our objective was to investigate this issue by measuring changes in carotid intima-media thickness (IMT). A total of 1,920 subjects received health examinations in 1999, and were followed up in 2007. Changes in IMT (follow-up IMT/baseline IMT × 100) were measured by ultrasonography. Our results showed that changes in IMT after eight years were significantly related to HDL-C (inversely, P < 0.05) and to LDL-C/HDL-C ratio (P < 0.05). When the LDL-C/HDL-C ratios were divided into quartiles, analysis of covariance showed that increases in the ratio were related to IMT progression (P < 0.05). This prospective study demonstrated the LDL-C/HDL-C ratio is a better predictor of IMT progression than HDL-C or LDL-C alone.

Plasma aldosterone levels and development of insulin resistance: prospective study in a general population.

Aldosterone plays a role in hypertension, and hypertension is prevalent in patients with insulin resistance. Cross-sectional studies have reported that plasma aldosterone levels are higher in patients with insulin resistance. However, it is not known whether plasma aldosterone levels predict the development of insulin resistance. Subjects of the present study were 1235 local residents (490 men and 745 women) who participated in health screenings in Japan in 1999. Plasma aldosterone levels were measured by radioimmunoassay. We investigated the cross-sectional relationship between plasma aldosterone levels and insulin resistance (homeostasis model assessment index ≥1.73 according to the diagnostic criteria used in Japan) in 1088 nondiabetic participants. At the 10-year follow-up, 141 subjects had died, and 260 subjects refused re-examination. We performed a prospective analysis of 564 subjects to predict incident insulin resistance. We found a significant (P<0.001) cross-sectional relationship between plasma aldosterone and homeostasis model assessment index at baseline. In the prospective analysis, a significantly higher (P<0.05) relative risk (1.71 [95% CI: 1.03-2.84]) was observed in the highest tertile versus lowest tertile of plasma aldosterone for the development of insulin resistance, after adjustment for confounding factors. This 10-year prospective study demonstrated that plasma aldosterone levels predicted the development of insulin resistance in a general population.

High level of plasma endothelin-1 predicts development of hypertension in normotensive subjects.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor derived from the endothelium. However, most large scale cross-sectional studies in humans have indicated no relationship between plasma ET-1 levels and hypertension. The present study was designed to determine whether high plasma ET-1 levels predict the development of hypertension. METHODS: A total of 1,492 subjects received a health examination in the Japanese cohort of Seven Countries Study in 1999, when, we examined blood pressure (BP), body mass index (BMI), and blood chemistries. Data on fasting ET-1 were obtained from 1,451 individuals. Seven years later, 1,261 subjects (494 males and 767 females) were re-examined (follow-up rate = 87%). RESULTS: Of 814 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline, 222 subjects developed hypertension. We divided the baseline plasma ET-1 levels into quartiles. The odds ratio for the development of hypertension after 7 years was 1.79 (95% confidence interval (CI): 1.08-2.96) in the highest quartile vs. the lowest quartile of ET-1 level after adjustment for confounding factors. CONCLUSION: A high level of plasma ET-1 predicted the development of hypertension in normotensive subjects.

Higher heart rate may predispose to obesity and diabetes mellitus: 20-year prospective study in a general population.

BACKGROUND: Emerging evidence indicates an association between sympathetic activation and metabolic syndrome. However, sympathetic activation in metabolic syndrome may be a cause, consequence, or just epiphenomenon. To elucidate this issue, the predictive power of resting heart rate for the development of abnormal glucose and lipid metabolisms after 20 years was evaluated in a general population. METHODS: A total of 637 participants (>20 years old) underwent a health examination in 1979 including measurements of blood chemistries. Resting heart rate (bpm) was measured by an electrocardiogram. In 1999, all of the study participants again underwent a health examination, including electrocardiogram and blood chemistries. Because four of them had atrial fibrillation, and 19 subjects were taking antihypertensive medication in 1979, they were excluded from analysis. Therefore, a complete dataset of 614 subjects was available. RESULTS: As was reported in our previous article, in 1999 we found a linear and significant (P < 0.05) cross-sectional relationship between resting heart rate and a cluster of cardiometabolic risk factors (blood pressure (BP), free fatty acid (FFA), plasma glucose, and homeostasis model assessment (HOMA) index). Baseline higher heart rate (heart rate >or=80 bpm in 1979) predicted the development of obesity, diabetes mellitus (DM), and insulin resistance in 1999 after adjustments for age, sex, and other confounders. CONCLUSION: This is one of the first prospective reports demonstrating that higher heart rate may predispose to the development of obesity and DM, suggesting that the sympathetic nerve system may play a role in the development of obesity and DM.

Decreased high-density lipoprotein cholesterol level is an independent correlate of circulating tumor necrosis factor-alpha in a general population.

BACKGROUND: Recent studies implicate a pathophysiological role of tumor necrosis factor-alpha (TNF-alpha) in atherosclerosis, thus suggesting that serum TNF-alpha levels may be one of the biomarkers for future cardiovascular events. However, which anthropometric, metabolic, and inflammatory variables could regulate circulating TNF-alpha levels in humans is not fully understood. In this study, we examined the independent determinants of serum TNF-alpha levels in a Japanese general population. HYPOTHESIS: Anthropometric, metabolic , and inflammatory variables could regulate TNF-alpha. METHODS: A total of 213 Japanese subjects underwent a complete history, physical examination, and determination of blood chemistries, including TNF-alpha levels. Univariate and multivariate analyses were applied for the determinants of TNF-alpha levels. RESULTS: The average TNF-alpha levels were 13.4 +/- 0.81 pg/ml in males and 13.9 +/- 4.5 pg/ml in females, respectively. Univariate analysis showed that TNF-alpha levels were associated with age (P = 0.007), body mass index (P = 0.034), waist circumference (<0.001), high-density lipoprotein cholesterol (HDL-C; inversely, P < 0.001), triglycerides (P < 0.001), creatinine (P < 0.001), uric acids (P < 0.001), insulin (P = 0.008), homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.015), high sensitivity C-reactive protein (hs-CRP; P < 0.001), and fibrinogen (P = 0.009). By the use of multiple stepwise regression analyses, HDL-C (inversely, P < 0.001) and hs-CRP (P < 0.001) remained significant and were independently related to TNF-alpha levels (R2 = 0.153). CONCLUSIONS: The present study is the first demonstration that besides hs-CRP, a decreased HDL-C level is an independent determinant of circulating TNF-alpha in the Japanese general population. Elevation of TNF-alpha may partly explain the increased risk of cardiovascular events in patients with low HDL-C levels.

Factors associated with serum high mobility group box 1 (HMGB1) levels in a general population.

High mobility group box 1 (HMGB1), a nonhistone chromatin-associated protein, is implicated as a mediator of both infectious and non-infectious inflammatory conditions. Clinical research on this protein in humans just has begun; serum HMGB1 was reported to be elevated in a small number of critically ill patients suffering from sepsis. However, the kinetics, distribution and factors associated with circulating HMGB1 are unknown in a general population. In this study, we examined these issues in a large population of healthy subjects. Fasting blood samples were obtained from 626 subjects (237 males and 389 females). HMGB1 levels showed a skewed distribution with a mean of 1.65 +/- 0.04 ng/ml. Multiple stepwise regression analyses found that white blood cell (WBC) counts (P = .016) and the soluble form of receptor for advanced glycation end products (sRAGE; P < .001, inversely), which is also known to be a receptor for HMGB1, were independently associated with HMGB1 levels. We demonstrated for the first time that circulating HMGB1 levels were inversely associated with sRAGE levels in a general population. Because RAGE is involved in HMGB1 signaling, our present study suggests that sRAGE may capture and eliminate circulating HMGB1 in humans.

Low-density lipoprotein levels are one of the independent determinants of circulating levels of advanced glycation end products in nondiabetic subjects.

BACKGROUND: Nonenzymatic modification of proteins by reducing sugars leads to the formation of advanced glycation end products (AGEs), whose process has been reported to progress under diabetes. Recently, diet has been found to be a major environmental source of proinflammatory AGEs in humans. Further, fats or meat-derived products processed by high heat such as broiling have been shown to contain more AGEs than carbohydrates boiled for longer periods. Since circulating levels of low-density lipoprotein cholesterol (LDL-C) are also regulated by dietary cholesterol, it is conceivable that intake of cholesterol-rich foods could regulate serum levels of AGEs in humans. In this study, we investigated whether LDL-C levels are one of the independent determinants of circulating AGEs levels in a nondiabetic general population. METHODS: A total of 170 nondiabetic Japanese subjects underwent a complete history, physical examination, determination of blood chemistries, and serum AGEs. RESULTS: Univariate analysis showed that AGEs levels were associated with LDL-C (P < 0.05) and fasting plasma glucose levels (P < 0.05). By the use of multiple stepwise regression analyses, LDL-C (P < 0.01) and fasting plasma glucose levels (P < 0.05) remained significant and were independently related to AGEs levels (R2 = 0.069). CONCLUSIONS: The present study is the first demonstration that LDL-C levels are one of the independent determinants of serum levels of AGEs in a nondiabetic general population. Intake of cholesterol-rich foods may regulate serum levels of AGEs in nondiabetic subjects.

Serum dehydroepiandrosterone sulfate levels predict longevity in men: 27-year follow-up study in a community-based cohort (Tanushimaru study).

OBJECTIVES: To determine whether serum dehydroepiandrosterone sulfate (DHEAS) levels could predict longevity in residents. DESIGN: Prospective community-based cohort study. SETTING: Community. PARTICIPANTS: Nine hundred forty subjects (396 men, 544 women; aged 21 to 88) underwent a health examination in 1978. Serum DHEAS levels were measured according to radioimmunoassay at baseline in all subjects, and subjects were followed periodically until 2005. RESULTS: Baseline DHEAS levels were higher in men than in women and decreased with age in both sexes. In a Cox proportional hazards model, age, DHEAS (inversely), blood pressure, and fasting plasma glucose were significantly associated with shorter longevity in men but not in women. Of these variables, high DHEAS levels in men were the strongest predictor of longevity (beta=-2.032, hazard ratio=0.131, 95% confidence interval=0.029-0.584 in the Cox proportional hazards model after adjustment for age). The Kaplan-Meier survival curve, stratified according to tertiles of DHEAS levels, in men after adjustments for age, systolic blood pressure, and fasting plasma glucose showed significantly (log-rank stat =10.6; P<.001) greater longevity in the highest group (200 microg/dL) than in the moderate (130-199 microg/dL) or lowest groups (129 microg/dL). CONCLUSION: This 27-year study in a community-based cohort indicated that DHEAS level may be a predictor of longevity in men, independent of age, blood pressure, and plasma glucose.